Bis-phenoxy compounds

ABSTRACT

Compounds of the formula h WHEREIN Z and Z&#39;&#39; are hydroxy and Y and Y&#39;&#39; are H, -COCH3, or COOR&#39;&#39; (R&#39;&#39; being an alkyl group) are used to prepare compounds of the formula AND THERAPEUTICALLY ACCEPTABLE SALTS, ESTERS AND AMIDES THEREOF, WHEREIN R1, R2, R3, R4, R5 and R6 are the same or different and each is H or halogen, lower alkyl, hydroxy, lower alkoxy, substituted lower alkyl or substituted lower alkoxy, and X is a saturated or unsaturated, substituted or unsubstituted, straight or branched polymethylene chain which may be interrupted by one or more carbocyclic rings or oxygen-containing heterocyclic rings, oxygen atoms or carbonyl groups. The latter compounds are useful as inhibitors of certain antigen-antibody reactions, being particularly useful for the relief and prophylaxis of asthma.

Uited States -atent Fitzmaurice et al.

' [151 3,686,320 14 1 *Aug. 22, 1972 [54] BIS-PHENOXY COMPOUNDS [72]Inventors: Colin Fitzmaurice; Thomas Brian Lee, both of Cheshire,England [73] Assignee: Fisons Pharmaceuticals Limited,

Loughborough, England 21 Appl. N0.2 762,638

Related US. Application Data [62] Division of Ser. Nos. 536,281, March22, 1966, Pat. No. 3,419,578, and Ser. No. 765,722, July 30, 1968.

[52] [1.8. Cl. ..260/592, 167/54, 167/55, l67/65, 260/345'2, 260/340.6,260/473, 260/520, 260/613, 424/ 10, 424/278 [51] Int. Cl ..C07c 49/78[58] Field of Search ..260/592 [56] References Cited UNITED STATESPATENTS 3,450,772 6/1969 Bridger et al ..260/592 3,519,652 7/1970Fitzmurice et al ..260/592 Primary Examiner-Daniel D. HorwitzAtt0rney-Wenderoth, Lind & Ponack [57] ABSTRACT Compounds of the formulaR1 R Y Y a Ra Ra wherein Z and Z are hydroxy and Y and Y are H, CO CH orCOOR (R being an alkyl group) are used to prepare compounds of theformula and therapeutically acceptable salts, esters and amides thereof,wherein R, R R, R", R and R are the same or different and each is H orhalogen, lower alkyl, hydroxy, lower alkoxy, substituted lower alkyl orsubstituted lower alkoxy, and X is a saturated or unsaturated,substituted or unsubstituted, straight or branched polymethylene chainwhich may be interrupted by one or more carbocyclic rings oroxygencontaining heterocyclic rings, oxygen atoms or carbonyl groups.The latter compounds are useful as inhibitors of certainantigen-antibody reactions, being particularly useful for the relief andprophylaxis of asthma.

4 Claims, N0 Drawings '1 BlS-PHENOXY COMPOUNDS This application is adivisional application of application Ser. No. 536,281, filed Mar. 22,1966, now U. S. Pat. No. 3,419,578, and Ser. No. 765,722, filed July 30,1968, the latter application being a divisional application of theformer.

This invention is concerned with improvements in or relating to newchemical compounds and pharmaceutical compositions containing them.

It has now been found that certain new chromone derivatives, ashereinafter defined, possess special activity as inhibitors of theeffects of certain types of antigcn-antibmly reaction, as evidenced, forexample, by in vivo tests.

According to the invention, therefore, there are provided as newcompounds bis-chromonyl compounds of the formula:

and functional derivatives thereof, in which R, R R R, R and R are thesame or different and each is a hydrogen or halogen atom (eg a chlorine,bromine, iodine or fluorine atom), a lower alkyl (e.g. a methyl, ethyl,propyl, isopropyl, butylor tertiaryl butyl group), hydroxy, lower alkoxy(e. g. a methoxy, ethoxy, propoxy, isopropoxy, butoxy or tertiary butoxygroup) or substituted lower alkyl or lower alkoxy group, (for example ahydroxyloweralkoxy, loweralkoxyloweralkoxy, carboxyloweralkoxy,hydroxyloweralkyl or haloloweralkyl such as chloro-, bromo-, iodoorfluoro-loweralkyl) and X is a saturated or unsaturated, substituted orunsubstituted, straight or branched polymethylene chain which may beinterrupted by one or more carbocyclic rings or oxygen containingheterocyclic rings, (e.g. benzene, dioxan, tetrahydrofuran, ordihydropyran ring Oxygen atoms or carbonyl groups.

In general, it is preferred that not more than one of R R and R and notmore than one of R, R and R isv other than hydrogen.

Accordingly a preferred embodiment of the invention is constituted bybis-chromonyl compounds of the formula:

o l X l Mj kl H020 o 4302 and functional derivatives thereof, in whichR" and a" and functional derivatives thereof, in which X has the meaningdefined above.

The group X may be any of a wide variety of groups. Thus for example, itmay be a straight or branched saturated or unsaturated hydrocarbonchain. Further, X may be such a chain interrupted by one or more oxygenatoms, carbonyl groups or carbocyclic or heterocyclic rings and may besubstituted by one or more halogen atoms (e.g. chlorine, bromine, iodineor fluorine atoms), orhydroxy or lower alkoxy (e.g. methoxy, ethoxy,propoxy, isopropoxy, butoxy, tertbutoxy, etc) groups. Specific examplesof the group X are groups of the formulae:

omf CHr-C-CHz, -CHzCHOHCH2- 0 :11.01

The group X is preferably a straight or branched hydrocarbon chain,which may be interrupted by one or more oxygen atoms, and contains fromthree to seven carbon atoms. Desirably such a chain is substituted byone or more hydroxyl groups, a particularly preferred chain being the2-hydroxy-trimethylene chain (-CH -CHOHCl-i The chain -O-X-O- may linkdifierent or corresponding positions on the chromone molecules.

A'particularly preferred compound according to the invention, in view ofits activity, is l,3-bis(2-carboxychromon-S-yloxy)-2-hydroxypropane ofthe formula:

0 1 COzH l CH1 +HOH (Hi: (I) i I and its functional derivatives.

Functional derivatives of the compounds according to the inventioninclude salts, esters and amides of one or more of the carboxylic acidfunctions present and esters of any hydroxylic functions present.

Salts of the bis-chromonyl compounds which may be mentioned are saltswith physiologically acceptable cations, for example, ammonium salts,metal salts such as alkali metal salts (e.g. sodium, potassium andlithium salts) and alkaline earth metal salts (e.g. magnesium andcalcium salts) and salts with organic bases, e.g., amine salts such as'piperidine, triethanolamine and diethylaminoethylamine salts.

Esters which may be mentioned include simple alkyl esters (e.g. methyl,ethyl, propyl, isopropyl, butyl and tertiary butyl esters) and amideswhich may be mentioned include simple amides (for example amideswithammonia and lower alkylarnines such as methylarnine, ethylamine etc) andmore complex amides with amino acids such as glycine.

The new bis-chromonyl compounds according to the invention have beenshown to inhibit the release and/r action of toxic products which arisefrom the combination of certain types of antibody and specific antigen,e.g., the combination of reaginic antibody with specific antigen. Inman, it has been found that both subjective and objective changes whichresult from the inhalation of specific antigen by sensitized subjectsare markedly inhibited by prior administration of the new bischromonylcompounds. Thus the new compounds are of great value in the prophylactictreatment of extrinsic allergic asthma. It has also been found that thenew bischromonyl compounds are of value in the prophylactic treatment ofso-called intrinsic asthma (in which no sensitivity to extrinsic antigencan be demonstrated).

It has also been found that in certain virus/antibody neutralizationsystems the new bis-chromonyl compounds enhance the neutralizingcapacity of the antiserum, and thus the new compounds mayfind use in thetreatment of viral infections.

According to a further feature of the invention, therefore, there isprovided a pharmaceutical composition comprising a bis-chromonylcompound according to the invention, preferably in the form of a salt,in association with a pharmaceutical carrier or diluent. There is alsoprovided a process for the manufacture of a pharmaceutical compositionwhich comprises mixing a bis-chromonyl compound with a carrier ordiluent.

The nature of the composition and the pharmaceutical carrier or diluentwill, of course, depend upon the desired route of administration, i.e.orally, parenterally or by inhalation.

The compositions according to the invention are especially useful forthe prophylactic treatment of asthma, i.e., the compositions areadministered to the patient at regular intervals (e.g. 4-6 hourly) inorder to inhibit the effects of asthmatic attacks from which the patientmay suffer. When employed in this manner, the dosage of composition ispreferably such that from 150 mg. of active compound are administered tothe patient at each administration.

In general, for the prophylactic treatment of asthma, the compositionswill be in a form suitable for adminis tration by inhalation. Thusthecompositions may comprise a suspension or solution of the activeingredient in water for administration by means of a conventionalnebulizer. Alternatively the compositions may comprise a suspension orsolution of the active ingredient in a conventional liquified propellantsuch as dichlorodifluoromethane or chlorotrifluorethane to beadministered from a pressurized container. The compositions may alsocomprise the solid active ingredient diluted with a solid diluent, e.g.lactose, for administrasolutions in pressurized propellants willcontain, for example, about 2 percent of the active bis-chromonylcompound. However, where the composition comprises the solidbis-chromonyl compound diluted with a solid diluent, the diluent may bepresent in less, equal or greater amount than the solid activeingredient, for example the diluent may be present in an amount of from50 to percent by weight of the solid active ingredient.

Theinvention also includes its scope a method of inhibiting the effectsof the antigen-antibody reaction which comprises the prior applicationto the area of the antigen-antibody mechanism a therapeuticallyeffective amount of a bis-chromonyl compound according to the invention.

According to a particular embodiment, the invention is for a method ofrelieving or preventing allergic airwayobstructionwhichcomprisesadministering to the patient a therapeuticallyeffective amount -(e.g. 1-50 mg) at suitable intervals, of abis-chromonyl compound according to the invention, particularly in theform of a salt. 7

The new compounds according to the invention are prepared by linkingtogether two chromone-Z-carboxylic acids or precursors therefor. 1

According to a further feature of the invention, therefore, there isprovided a process for the preparation of bis-chromonyl compounds of theformula:

0 II R H U I I 11020 0/ X 0 4302.11

' R2 R3 R5 and functional derivatives thereof, in which R R R3, R, R andR have the meanings defined above, which comprises reacting in one ormore stages,

S and c. a compound of the formula:

A X B.

or a chain (in which W is a carboxylic acid group orv a functionalderivative thereof or a group convertible to a carboxylic acid group ora functional derivative thereof), Y and Z have the same definition as Yand Z above and may be the same or different; and A and B are the sameor different and each is a group capable of reacting with a hydroxylgroup to form an ether linkage, or one of A and B is a group capable ofbeing converted to such a reactive group; and X is such that the group-A- XB' (in which A and B are the residues of A and B after theformation of ether linkages) has the same meaning as X; toform acompound of the formula:

tion may be carried out in one or more stages. Thus, it may be carriedout in two stages as follows:

This procedure will generally be adopted when the two chromone moietiesof the desired bis-chromonyl compound are different, i.e., when R, R andR are different from R, R and R". in the two stage process, thegroupings Y and Z or Y and Z may be modified at an intermediate stagebut, in general, it is not preferred to follow this route. When the twochromone moieties of the desired bis-chromonyl compound are the same thereaction may be carried out in two stages, or preferably, if Y and Zhave the same meanings as Y and Z, in one stage, i.e., by reaction of acompound of the formula:

with a compound of the formula:

When the reaction is carried out in two stages the com- 7 pound AX-B maybe such that one of A and B is a group capable of being converted to anether linkage forming group. When both A and B are ether linkage forminggroups, the first stage of a two stage reaction will, of course, becarried out using substantially equimolecular proportions of the twocompounds.

Examples of groups A and B capable of reacting with a phenolic hydroxylgroup, such that an ether linkage is formed by X and the hydroxyl group,include halogen atoms, e.g., chlorine, bromine or iodine atoms, or otheranion forming groups such as tosylate 'or methane sulphonate groups.Where the group A contains a hydroxy group beta to the subsequentlyformed ether linkage the group A or B may represent an epoxide group,giving rise to a residue A or B of CH CHOH-.'The groups A and B may bethe same or different; thus a compound AX'--B capable of yielding a2-hydroxy-trimethylene linkage is the compound:

- hydroxy-trimethylene linkage is allyl bromide.

The reaction between the chromone moiety or precursor therefor and thelinking compound A-X B will be carried out under the conditions normallyemployed for the formation of ether linkages. Thus, the reaction willgenerally be carried out in the presence of aqueous alkali or a solventsuch as acetone or dioxan and at elevated temperature. Where the etherlinkage formation is carried out byreaction of the aromatic hydroxygroup and a compound AX-B in which A and/or B is an anion forming group(e.g. halogen, methanesulphonate etc) the reaction is desirably lycarried out in the presence of an acid binding agent such as an alkalimetal carbonate (e.g. sodium carbonate or potassium carbonate) or anorganic acid binding agent such as pyridine, diethylaniline ortriethylamine. Where A and/or B is an epoxide group the ether formingreaction may be conveniently carried out in the presence of a suitablecatalyst, EEG. in the presence of a quaternary ammonium hydroxide.

The conversion, if necessary, of Y and Z and/or Y' and Z to the desiredchain CO-CH C(COOH) O or functional derivative thereof will be carriedout simultaneously if Y and Z are the same as Y and Z' and in separatestages if Y and Z are not the same as Y' and 2'. It is, however,generally preferred that Y and Z are the same as Y' and Z since thisreduces the number of chemical stages involved.

In the following description of methods of converting Y and Z to thedesired chain -COCH C(COOH) --O or functional derivatives thereofreference will only be made to one chrornone moiety but it will, ofcourse, be understood that where Y and Z are the same as Y and Z theprocess will act simultaneously on both moieties.

A preferred process involves the conversion of the compound in which Yis a group -COCH and Z is a hydroxy group (i.e., a substitutedo-hydroxyacetophenone) to a chain -COCH C(COOR) O- (in which R is ahydrogen atom or an alkyl group); 1e,

' where R is the alkyl group of the dialkyl oxalate, which intermediatemay be cyclized directly by heating or may be isolated and cyclized byheating in a suitable solvent in the presence of a cyclization agentsuch as an acid.

When the oxalic acid derivative is of the formula:

in which R" is an alkyl group, e.g. ethyl ethoxydichloroacetate, thereactants are desirably employed in substantially equimolecularproportions and the reaction is conveniently carried out in the presenceof a metallic catalyst such as finely divided metallic platinum,palladium or ruthenium. When the oxalic acid derivative is of theformula:

Hal CO COOR' pound of the formula:

This reaction may be carried out by a number of routes. A preferredroute involves the reaction of the ohydroxyacetophenone with an oxalicacid derivative of the formula:

in which R is a halogen atom or a group ()R (in which R is an alkylgroup), R and R" are both halogen atoms and R is a group OR or R and R"together represent an oxygen atom O)'and R is a halogen atom or a groupOR.

Thus a particularly preferred process involves reaction of theortho-hydroxy-acetophenone witha dialkyl oxalate, such as diethyloxalate, preferably in the presence of a condensation agent such as analkali metal alkoxide, e.g., sodium ethoxide, sodamide, metallic sodiumor sodium hydride and conveniently in the presence of an organic solventsuch as ether, dioxan, ethanol or benzene. This process goes through anintermediate of the formula:

R Rs

Jar-002R which may then be oxidatively cycli zed'to the desiredchromone-2-carboxylic acid. Non-oxidative cyclization gives rise to thecorresponding chromanone which may be converted to the chromone asdescribed below.

A different route for the formation of the desired chromonyl compoundinvolves the conversion of Y and Z (when Y is -COCH and Z is -OH) to anintermediate of the formula:

in which V is a group convertible to a carboxylic acid, or functionalderivative thereof, and subsequent conversion of the group V to acarboxylic acid group or functional derivative thereof.

Examples of the group V are the nitrile group which 5 may be hydrolyzedto a carboxylic acid group and o-hydroxy-acetophenone by condensationwith an alkyl acetate, in a similar manner to the condensation describedabove for the dialkyl oxalate.

The 2-methyl chromone also serves as an intermediate in the preparationof a number of other oxidizable derivatives. Thus, the Z-methyl chromonemay be converted into the corresponding 2-halomethylchromone, e.g., byreaction with hydrogen chloride and manganese dioxide in boiling aceticacid to produce a 2-chloromethyl chromone or by reaction with bromineinacetic acid to yield the 2-bromomethylchromone. The 2-halomethylchromone may be oxidized to the corresponding chromone-Z-carboxylicacid, for example, with potassium permanganate, or may be hydrolyzed,using, for example, moist silver oxide, to p give the 2-hydroxymethylchromone which may then be oxidized to the chromone-Z-carboxylic acid,for example, using chromium trioxide as oxidizing agent in the presenceof acetic acid and at ambient temperature or below. 7

The 2-methyl chromone may further be reacted withp-nitrosodimethylaniline and the reaction product hydrolyzed with dilutemineral acid to give the corresponding 2-formyl-chromone which may beoxidized to the corresponding chromone-2-carboxylic acid using, forexample, chromium trioxide as reagent.

Condensation of the Z-methyI-chromone with a benzaldehyde in thepresence of a condensation catalyst gives the 2-styryl chromone whichmaybe oxidized to the corresponding chromone-Z-carboxylic acid, forexample using potassium permanganate.

A number of the chromone derivatives, other than the 2-methyl chromone,convertible to the chromone- 2-carboxy1ic acid may be prepared directlyfrom the ohydroxy-acetophenone.

Thus, the 2-formyl chromone may be prepared by condensation of adialkoxy acetate of the formula:

in which R and R have the meanings defined above, e.g., ethyl diethoxyacetate, with the o-hydro'xyacetophenone to yield an' acetal which maysubsequently be hydrolyzed, e.g., with dilute mineral acid, to thealdehyde, which may subsequently be oxidized to thecarboxylic acid.hydrolyzed the chromone The 2-formyl chromone may also serve as astarting point for the preparation of the 2-cyano chromone. Thus, the2-formyl chromone may be reacted with hydroxylamine to yield the2-oximino-chromone which may then be dehydrated to the 2-cyanochromonewhich may then be hydrolysed to the chromone-Z-carboxylic'acid or amidethereof under acid conditions.

The 2-styryl chromone may be prepared from the ohydroxy-acetophenone byreaction with sodium cinnamate and 'cinnamic anhydride (i.e. by theKostanecki reaction) or by reaction with a cinnamoyl halide, e.g.,cinnamoyl chloride, in the presence of an acid binding agent to yieldthe cinnamate ester of the o-hydroxyacetophenone followed by treatmentwith a base, e.g. potassium carbonate, in the presence of an inertsolvent such as toluene or benzene to give an alphadiketone of theformula:

which is subsequently cyclized either by direct heating or by heating inthe presence of a cyclization agent (Baker Venkataraman reaction).

The 2-vinyl chromone may likewise be prepared from theo-hydroxy-acetophenone by reaction with ethyl acrylate.

The compound in which Y is a hydrogen atom and Z is a hydroxyl group,i.e., the phenol of the formula:

may be converted to the corresponding chromone-2- carboxylic acid by anumber of methods.

For example, the chromone-2-carboxylic acid may be prepared by reactionof acetylene dicarboxylic acid or a dialkyl ester thereof, e.g., diethylacetylene dicarboxylate, with the phenol or with an alkali metal phenatethereof. 4

Where the acetylene dicarboxylic acid or ester thereof is reacted withthe alkali metal phenate, i.e., the compound of the formula:

in which M is an alkali metal atom, the reaction is desirably carriedout'in the presence of an inert organic solvent or diluent to yield afumarate of the formula:

which is then, if necessary after hydrolysis, cyclized to the desiredchrorndne-Z-carboxylic acid, for example by heating in the presence of acyclization catalyst such as sulphuric acid. In a modification of thisprocess the acetylene dicarboxylic acid or ester thereof is replaced bya halo-fumaric acid or an ester thereof, e.g., diethyl chlorofumarate,or by a dihalosuccinic acid or ester thereof.

The chromone-Z-carboxylic acid may also be prepared from the phenol byreaction with a compound such as ethyl ethoxalylacetate.

in another method the phenol may be esterified, e.g. with ethylethoxalyl chloride to give an ester of the formula:

which may subsequently be cyclized in the presence of acetic acid or aderivative thereof (e.g., ethyl acetate or acetyl chloride) to give hedesired chromone-Z-carboxylic acid.

The phenol may alternatively be condensed with maleic anhydride to givea compound of the formula:

which may then be oxidatively cyclized to the desiredchromone-Z-carboxylio acid. Non-oxidative cyclization gives rise to thecorresponding chromanone which may then be converted to the chromone asdescribed below.

The compound in which Z is a hydroxyl group and Y is a group -COOR' i.e.the substituted salicylic acid ester of the formula:

-ooo1v may be converted to the desired chromone-2-carboxylic acid byreaction with a pyruvate ester of the formula:

CH CO' COOR' if desired in the presence of a condensation agent such asan alkali metal alkoxide (e.g. sodium ethoxide), sodamide, metallicsodium or sodium hydride, and preferably in the presence of an organicsolvent such as ethanol or dioxan.

' When Y and Z together form a chain in which W is the desiredcarboxylic acid group or functional derivative thereof, obviously nomodification of Y and Z will be necessary. When W is group convertibleto a carboxylic acid group, or a functional derivative thereof, it willhave the same meaning as defined for V above and may be converted to thecorresponding carboxylic acid group as described for V above. When Y andZ together form a chain i.e., a chromanone, the group W will remainunchanged or be'converted to a carboxylic acid group as necessary andfurther the chromanone will need to be dehydrogenated to thecorresponding chromone; which dehydrogenation may be carried out eitherbefore or after any conversion of W.

The dehydrogenation of the chromanone of the formula:

may, for example, be effected using selenium dioxide or other suitabledehydrogenating agents such as palladium black or chloranil.

. Thus, the chromanone may be bromina'ted using N- bromosuccinimide inan inert solvent or by treatment with pyridinium perbromide in an inertsolvent such as chloroform in the presence of a free radical catalystsuch as benzoyl peroxide, to yield the 3-bromo derivative whichmay besubsequently dehydrobrominated.

- The processes described above generally lead to the formation of thechromone-2-carboxylic acids as such or in the form of their esters.These may be readily converted to other functional derivatives, e.g.,salts or amides, by conventional methods.

The majority of the intermediates produced by the linking of the twochromone moieties or precursors therefor are in themselves new.

According to the invention, therefore, there are provided as newcompounds, compounds of the formula:

in which R, R, R, R R B X, Y, Z, Y and Z have the meanings definedabove, provided that not more than one of Y and Z and Y and 2'represents a chain CO-Cl-l C(COOH)-O or a functional derivative thereofand further provided that when R, R R, R, R and R are hydrogen and Y andY are groups COCH and Z and Z are hydroxyl groups, X is not a group -CH-CHOHCH linking the two positions para to the groups Y and Y.

This invention also provides a process for the preparation of the newintermediates which comprises reacting in one or more stages:

a. a compound of the formula:

b. a compound of the formula:

R. Jill and (c) a compound of the formula:

A x'-' B 200 parts by volume of acetone for 72 hours. The acetonesolution was filtered and the solid residue was washed first withacetone and then with water. The combined acetone filtrate and washingswere evaporated leaving an oil which, on being boiled with ether, gavepale yellow crystals. These were combined with the first obtained solidand extracted with refluxing isopropanol in a Soxhlet extractor forseveral days to obtain 16.1 parts ofl,3-bis(2-acetyl-3-hydroxyphenoxy)propane as almost colorless crystalsmelting between 184 and 185 C. Analysis:

Found C, 65.4; H, 5.68%

c t-1, 0, requires: C, 66.2; H, 5.81% b. Diethyl ester of1,3-bis(2-carboxychromon-5-yloxy)propane A solution of 6.9 partsl,3-bis( 2 acetyl-3-hydroxyphenoxy) propane in parts by volume ofdiethyl oxalate was added to a solution of 3 parts sodium in 30 parts byvolume of ethanol and 50 parts by volume of benzene and the mixture washeated gently under reflux for hours. It was then poured into a largevolume of ether and the precipitated solid was filtered, washed withether and dried. It was then dissolved in water and acidified to obtaina sticky solid. This was boiled with about 50 parts of ethanolcontaining a catalytic amount of hydrochloric acid for about 10 minutes,when crystals began to form. The solution was cooled and filtered toobtain 7.4 parts of solid melting between 178 and 180 C. This wasrecrystallized from 200 parts by volume of a 1:2 mixture of benzene andethanol to obtain a first crop of 4.5 parts of the diethyl ester ofl,3-bis( 2-carboxychromon-5-yloxy)propane, melting between 182 and 183C. Analysis:

Found: C, 63.2; H, 4.60%

C H O requires: C, 63.7; H, 4.72% c. Disodium salt of1,3-bis(2-carboxychromon-5-y1oxy)p A suspension of 3 parts of thediethyl ester of 1,3- bis(2-carboxychromon-5-yloxy)propa.ne in 50 partsby volume of boiling ethanol was treated with 11.6 parts by volume of1.015N aqueous sodium hydroxide. Water was added until a clear solutionwas obtained. This was treated with charcoal, filtered and concentratedby boiling, with the occasional addition of more ethanol. On cooling 2.2parts of colorless crystals of the disodium salt of1,3-bis(2-carboxychromon-5-yloxy)propane monohydrate more were obtained.Analysis:

Found: C, 54.1; H., 2.86%

C H Na O H O requires: C, 53.7; H., 3.11% EXAMPLE 2 a. l ,3-Bis(2-acetyl-3-hydroxyphenoxy)-2-hydroxypropane By the method of Example 1(a) 10 parts of 2,6- dihydroxy-acetophenone, 4.6 parts potassiumcarbonate and 7.15 parts 1,3-dibromopropan-2-ol were reacted in acetoneto obtain 3 parts of pure 1,3-bis(2-acetyl-3-hydroxyphenoxy)-2-hydroxypropane as colorless crystals meltingbetween 165 and 166 C. Analysis:

Found: C, 63.5; H, 5.86%

C H O requires: C, 63.3; H, 5.56% b. 1,3-Bis(2-acetyl-3-hydroxyphenoxy)-2-hydroxypropane To a solution of 970parts of 2,6-dihydroxyacetophenone and 325 parts of epichlorohydrin in2,500 parts of hot isopropanol was added, with stirring under reflux, asolution of 233 parts of percent KOl-l in 2,500 parts of isopropanol andsufficient water (ca. parts) to dissolve the solid. The mixture washeated, with stirring, under reflux for 48 hours. Half the solvent wasthen distilled off and 5000 parts of water were added. The mixture wascooled and the solid filtered off and washed with isopropanol and ether.It was then recrystallized from 12,500 parts of isopropanol to obtain afirst crop of 380 parts and a second crop, after concentration, of 300parts of 1,3-bis(2-acetyl- 3- hydroxyphenoxy)-2-hydroxypropane identicalwith that obtained in Example 2 (a) above.

c. Diethyl ester of l,3-bis( 2-carboxychromon-5-yloxy 2-hydroxypropaneBy the method of Example 1 (b) 4.6 parts of 1,3-bis(2-acetyl-3-hydroxyphenoxy)-2-hydroxypropane were reacted withdiethyl oxalate and the product cyclized to obtain 4.4 parts of purediethyl ester of 1,3- bis(2-carboxychromon-S-yloxy)-2-hydroxypropane aspale yellow crystals melting between 180 and 182 from a mixture ofbenzene and petrol.

Analysis:

Found: C, 61.5; H, 4.61%

C H O requires: C, 61.8; H, 4.57%

d. Disodium salt of l,3-bis(2-carboxychromon-5-yloxy)-2-hydroxypropaneBy the method of Example 1 (c), 4 parts of the diethyl ester of1,3-bis(2-carboxychromon-5-yloxy)-2- hydroxypropane were saponified toobtain 3.2 parts of the disodium salt tetrahydrate as colorless crystalsfrom aqueous alcohol.

Analysis:

Found: C, 47.8; H, 3.8; Na, 7.7% c,,H,,Na,0 4H,o requires: C, 47.3; H,3.79; Na,

7.7% e. 1,3-Bis( 2-carboxychromon-5-yloxy)-2-hydroxypropane.

A solution of the disodium salt of1,3-bis(2-carboxychromon-S-yloxy)-2-hydroxypropane in water wasacidified and the precipitate was recrystallized from ethanol plus etherto obtain l,3-bis(2-carboxychromon-S-yloxy)-2-hydroxypropane monohydrateas colorless crystals melting with decomposition between 216 and 217.

Analysis:

Found: C, 56.7; H, 3.44%

c m o n o requires: C, 56.8: H, 3.70% Dehydration of the monohydrate invacuo at C gave the anhydrous acid melting between 241 and 242 C withdecomposition.

f. Calcium salt of 1,3-bis( 2-carboxychromon-5-yloxy)- 2-hydroxypropaneThe disodium salt of l,3-bis(2-carboxychromon-5- yloxy)2-hydroxypropane(0.8 parts) dissolved in the minimum volume of warm water was treatedwith a solution of 0.225 parts of calcium nitrate in a small volume ofwater, to obtain the sparingly soluble calcium salt. The mixture wascooled and filtered, and the solid was washed with cold water and driedat 1 10 C. Analysis:

Found: Ca, 7.19%

C H CaO 3l-I O requires: Ca, 7.14% g. Magnesium salt ofl,3-bis(2-carboxychromon-5- yloxy)2-hydroxypropane A suspension of 2parts of l,3-bis(2-carboxychromon-S-yloxy)-2-hydroxypropane in 20 partsof water was treated with 0.36 parts of magnesium carbonate. The mixturewas boiled with stirring until homogeneous, cooled, filtered and driedat 110 C to obtain 2.3 parts of the magnesium salt.

h. Dipiperidine salt of 1,3-bis( 2-carboxychromon-5-yloxy)-2-hydroxypropane A suspension of 2 parts ofl,3-bis(2carboxychromon-S-yloxy) -2-hydroxypropane in 20 parts of waterwas treated with 0.7 part of piperidine. The mixture was warmed underreflux until a clear solution was obtained after which it was cooled anddehydrated by freeze-drying to obtain 2.8 parts of the dipiperidine saltof 1 ,3-bis( 2-carboxychromon-5 -yloxy)-2-hydroxypropane.

Analysis:

Found: C, 59.0; H, 6.12; N, 4.00% C H NO '2l-I O requires: C, 59.1; H,5.67; N,

4. l 8% EXAMPLE 3 a. 1,4-Bis(2-acetyl-3-hydroxyphenoxy)but-2-ene By themethod of Example 1 (a), 15.2 parts of 2,6- dihydroxy-acetophenone werecondensed with 10.7 parts of 1,4-dibrombut-2-ene to obtain 6 parts of1,4- bis(2-acetyl-3-hydroxyphenoxy)but-2-ene melting between 145 and 146from acetone.

b. 1,4-Bis(2-carboxychromon-5-yloxy)but-2-ene By the method of Example 1(b), 5 parts of 1,4-bis( 2- acetyl-3-hydroxyphenoxy)but-2-ene werecondensed with diethyl oxalate to obtain 3 parts of the diethyl ester of1,4-bis(2-carboxychromon-5-yloxy)but-2-ene as yellow crystals meltingbetween 215 and 217 C from ethanol.

Analysis:

Found: C, 64.1; H, 4.69%

C H O, requires: C, 64.6; H, 4.6%

Saponification of 2 parts of the diethyl ester of 1,4-bis(2carboxychromon-5-yloxy)but-2-ene by the method of Example 1 gave1.5 parts of the disodium salt.

Acidification of an aqueous solution of this sodium salt gave the freeacid monohydrate, melting between 193 and 195.

Analysis:

Found: C, 59.6;H3.56%

(hi-1 0 11 0 requires: C, 59.7; H, 3.73% EXAWLE 4 1 1 2-bis(2-carboxychromon-5-yloxy)-2, 1 1 -dihydroxy- 4,9-dioxadodecane Asolution of 10 parts 2,6-dihydroxyacetophenone, 5.6 butane-1,4-dioldiglycidyl ether and 0.1 part of 40 percent aqueous solution ofbenzyltrimethylammonium hydroxide in 14 parts dioxan was heated at 100 Cin a sealed vessel for 60 hours. The dioxan was removed under reducedpressure leaving a thick yellow oil. This was extracted several timeswith boiling ether and the combined extracts were fractionallyprecipitated with petrol. The first fraction, which was about parts of aclear yellow oil, could not be crystallized or distilled but had aninfra-red spectrum consistent with that expected for1,12-bis(2-ace'tyl-3- hydroxyphenoxy)-2, ll-dihydroxy-4,9-dioxadodecane. This was condensed with diethyl oxalateby the method of Example 1 (b) to obtain 3 parts of the diethyl ester of1,12-bis(2-carboxychromon-5-yloxy)-2,l 1-

2.. dihydroxy-4,9-dioxadodecane as an oil. This oil was stirred andwarmed with a saturated aqueous solution of sodium bicarbonate untildissolved. The solution was filtered and acidified with dilutehydrochloric acid. The precipitate was dissolved in ethanol plus ethylacetate, treated with charcoal, filtered and precipitated with petroland the solid was recrystallized from acetone plus ether to obtain 1part of pure l,12-bis(2-carboxychromon-5-yloxy)-2, 1 l-dihydroxy-4,9-dioxadodecane dihydrate as colorless crystals meltingwith decomposition at C.

Analysis:

Found: C, 55.3; H, 5.24%

(3 15 0 211 0 requires: C, 55 .3; H, 5.22%

l ,12-Bis(2-carboxychromon-5-yloxy)-2,1 1 dihydroxy-4,9-dioxadodecanedihydrate (0.325 parts) was dissolved in a solution of 0.084 partssodium bicarbonate in parts water. The solution was filtered andfreeze-dried to obtain 0.3 parts of the disodium salt tetrahydrate.

Analysis:

Found: C, 48.7; H, 4.75%

C H Na O AH O requires: C, 49.3; H, 4.9% EXAMPLE 5 a.1,4-Bis(2-acetyl-3-hydroxyphenoxy)butane By the method of Example 1 (a)2,6-dihydroxyacetophenone was reacted with 1,4-dibromobutane to obtain1,4-bis( 2-acetyl-3-hydroxyphenoxy)butane melting between 219 and 221 Cfrom benzene. Analysis:

Found: C, 66.0; H, 6.0%

C d- 0 requires: C, 67.0; H, 6.2%

b. Diethyl ester of l,4-bis(Z-carboxychromon-S-yloxy)butane By themethod of Example 1 (b) 1,4-bis( 2-acetyl-3- hydroxy-phenoxy)butane wascondensed with diethyl oxalate to form the diethyl ester of1,4-bis(2-carboxychromon-5-yloxy)butane melting between and 199 C from amixture of ethyl acetate and isopropanol. Analysis:

Found: C, 62.4; H, 5.1%

C H O l-I O requires: 0, 62.3; H, 5.2%

c. 1,4-Bis(2-carboxychromon-5-yloxy)butane The diethyl ester ofl,4-bis(2-carboxychromon-5- yloxy)butane was hydrolyzed by heating withaqueous sodium bicarbonate until dissolved, filtering and acidifying thesolution. The precipitate was recrystallized from methanol to obtainpure l,4-bis(2-carboxychromon-5-yloxy)butane monohydrate melting between228 and 230 C.

Analysis:

Found: C, 58.6; H, 3.95%

C H O I-I O requires: C, 59.5; H, 4.2%

This acid was dissolved in an equivalent amount of sodium bicarbonatesolution and freeze-dried to obtain the disodium salt. EXAMPLE 6 l,5-Bis( 2-carboxychromon-5-yloxy )pentane 2,6-Dihydroxyacetophenone wasreacted with 1,5- dibromopentane as in Example 1(a) to obtain l,5-bis(2-acetyl-3-hydroxyphenoxy) pentane melting between 131 and 133 Cfrom benzene.

Analysis:

Found: C, 67.4; H, 6.3% C H Q, requires: C, 67.7; H, 6.5%

This diketone was condensed with diethyl oxalate as in Example 1(b) toobtain the diethyl ester of 1,5-bis( 2- carboxy-chromon-S-yloxy)pentane,melting between 150 and 152 C from ethanol.

Analysis:

Found: C, 64.6; H, 5.3%

C l-l O requires: C, 64.8; H, 5.3%

The ester was hydrolyzed as in Example 5(c) to obtain the acid as amonohydrate melting between 226 and 228 C from ethanol.

Analysis:

Found: C, 60.3; H, 4.7%

C H O H O requires: C, 60.2; H, 4.4%

The acid was subsequently converted to the disodium salt by the methodof Example 5(c). ELE 7 1 ,6-Bis( Z-carboxychromon-S-yloxy )hexane2,6-Dihydroxyacetophenone was reacted with 1,6- dibromohexane as inExample 1(a) to obtain 1,6-bis(2- .acetyl-3-hydroxyphenoxy) hexanemelting between 147.5 and 148.5 C from ethanol. Analysis: 7

Found: C, 68.1; H, 6.7%

C T-11 0,, requires: C, 68.4; H, 6.8% r

This diketone was condensed with diethyl oxalate by the method ofExample 1(b) to obtain the diethyl ester of1,6-bis(2-carboxychromon-5-yloxy)hexane melting between 154.5 and 155 Cfrom ethanol.

Analysis:

Found: C, 65.0; H, 5.4%

Q E- requires: C, 65.4; H, 5.5%

The ester was hydrolyzed as in Example (c) to obtain the acidmonohydrate melting between 228 and 230 C from dioxan.

Analysis:

Found: C, 60.2; H, 4.9%

C H O H O requires: C, 60.9; H, 4.7%

The disodium salt of the acid was subsequently prepared as in Example 5(c).

1 ,10-Bis(2-carboxychromon-5-yloxy)decane 2,6-Dihydroxyacetophenone wascondensed with 1,10-dibromodecane as in Example 1 (a) to obtain1,10-bis(2-acetyl-3-hydroxyphenoxy) decane melting between 102.5 and 104C from ethyl acetate.

Analysis:

Found: C, 70.0; H, 7.4%

C i-i 0, requires: 0, 70.6; H, 7.7%

This diketone was reacted with diethyl oxalate as in Example 1 (b) toobtain the diethyl ester of 1,10-bis( 2- carboxychromon-5-yloxy)decanemelting between 146.5 and 148 C from ethanol plus dioxan.

Analysis:

Found: C, 67.4; H, 6.45%

0 requires: C, 67.3; H, 6.3%

The ester was hydrolyzed by boiling with aqueous sodium bicarbonate toobtain the sparingly soluble disodium salt which was recrystallized fromwater. Analysis:

Found: C, 61.0; H, 5.2%

c,,N,,Na,o,, requires: 60.6; H, 4.7%

EXAMPLE 9 1 ,7-Bis( 2-carboxychromon-5-yloxy )-2,6-dihydroxy-4-oxaheptane l 8 2,6-Dihydroxyacetophenone was reacted with diglycidylether as in Example 4 to obtain l,7-bis( 2- acetyl-3-hydroxyphenoxy)tane melting between 129 and 131 C from ethyl acetate plus petrol.Analysis:

Found: C, 60.4; H, 6.3%

C l-i 0, requires: C, 60.8; H, 6.0%

This diketone was reacted with diethyl oxalate to obtain the bischromonediethyl ester as an oil which could not be crystallized, This ester washydrolyzed as in Example 5 (c) to obtain 1,7-bis( 2-carboxychromon-5-yloxy)-2,6-dihydroxy-4-oxaheptane monohydrate melting between 216 and218 C.

Analysis:

Found: C, 55.6; H, 3.4%

C i-1 0 14 0 requires: C, 55.7; H, 4.3%

The disodium salt was subsequently prepared as in Example 5 (c).

1 ,5-Bis(2-carboxychromon-5-yloxy )-3-oxapentane2,6-Dihydroxyacetophenone was condensed with 2,2-dibromo-diethyl ether,as in Example 1 (a) to obtain l,5-bis(2-acetyl-3-hydroxyphenoxy)-3-oxapentane melting between 120.5 and 121 ,5C from methanol.

Analysis:

Found: C, 63.5; H, 5.1%

C l-i 0, requires: C, 64.1; H, 5.9%

This was condensed with diethyl oxalate as in Example 1 (b) to obtainthe diethyl ester of 1,5-bis(2-carboxychromon-5-yloxy)-3-oxapentanemelting between 129 and 13 1 .5 C from methanol.

Analysis:

Found: C, 62.3; H, 4.9%

C i-I 0 requires: C, 62.4; H, 4.9%

The ester was hydrolyzed as in Example 5 (c) to obtain the acid meltingbetween 219 and 220 C from ethanol plus dioxan.

Analysis:

Found: C, 59.8; H, 3.9%

C H O requires: C, 59.8; H, 3.8%

The disodium salt of the acid was subsequently prepared as in Example 5(c).

EXAMPLE 11 l ,4-Bis('2-carboxychromon-5-yloxy )-2,3-dihydroxybutane2,6-Dihydroxyacetophenone was reacted with l,2:3,4-bisepoxybutane as inExample 4 to obtain 1,4-bis(2-acetyl-3-hydroxyphenoxy)-2,3-dihydroxybutane, melting between 21 1and 212 C from dioxan. Analysis:

Found: C, 61.0; H, 5.7%

G l-1 0 requires: C, 61.5; H, 5.7%

This was condensed with diethyl oxalate as in Example 1 (b) to obtainthe diethyl ester of 1,4-bis(2-carboxychromon-S-yloxy)-2,3-dihydroxybutane melting between 224 and226 C.

Analysis:

Found: C, 59.2; H, 4.6%

- C l- 0, requires: C, 60.6; H, 4.7%

This was hydrolyzed by the method of Example 5 (c) to obtain the acid asa dihydrate melting between 260 and 262 C.

Analysis:

Found: C, 54.0; H, 3.7% C H O 2H O requires: C, 54.0; H, 4.1%

2,6-dihydroxy-4-oxahep- W12 This was subsequently converted to the saltas in Example 5 (c). EXAMPLE 12 between 207.5 and 208.5 C from methanol.

Analysis:

Found: C, 63.4; H, 5.8%

C H O requires: C, 64.2; H, 5.9%

This was condensed with diethyl oxalate as in Example 1 (b) to obtainthe diethyl ester of 1,4-bis( 2-carboxychromon-S-yloxy)-2-hydroxybutanemelting between 216 and 217 C from a mixture of chloroform, ethylacetate and petrol.

Analysis:

Found: C, 62.7; H, 5.2%

c n o requires: C, 62.4; H, 4.9%

This was hydrolyzed as in Example 5 (c) to obtain the acid as amonohydrate melting between 226 and 227 C.

Analysis:

Found: C, 57.1; H, 3.9%

C H O H O requires: C, 57.6;H, 4.0%

This was subsequently converted to the disodium salt as in Example 5(c).

EXAMPLE 13 1 ,5-Bis( 2-carboxychromon-7-yloxy )pentane Ethyl7-hydroxychromone-2-carboxylate was condensed with one half equivalentof 1,5-dibromopentane by heating in acetone in presence of potassiumcarbonate to obtain the diethyl ester ofl,5-bis(2-carboxrychromon-7-yloxy)petane melting between 148 and 150 Cfrom ethanol.

Analysis:

Found: C, 64.6; H, 5.3%

C I-I O requires: C, 64.8; H, 5.3%

This ester was hydrolyzed as in Example 5 (c) to obtain the acid meltingbetween 283 and 284 C. Analysis:

Found: C, 61.8; H, 4.2%

C l-[ requires: C, 62.4; H, 4.2%

The acid was subsequently converted to the disodium salt by the methodof Example (0).

EXAMPLE 14 1 l0-Bis( 2-carboxychromon-5-yloxy)-3 ,8-dioxa-4,7-dioxodecane Ethyl 5-(2-hydroxyethoxy)chromone-2-carboxylate (1.4 parts)and 0.4 parts succinyl chloride were dissolved in chloroform and treatedwith 0.5 parts pyridine. The mixture was heated under reflux for 16hours. The chloroform solution was washed with dilute hydrochloric acid,sodium carbonate solution and water and dried over sodium sulphate. Thechloroform was distilled to leave an oil which was solidified bytrituration with petrol. It was recrystallized from ethanol to obtain0.2 parts of the diethyl ester of 1,10-bis(2-carboxychromon-5-yloxy)-3,8-dioxa-4,7-dioxodecane melting between144 and 146 C.

Analysis:

Found: C, 60.5; H, 4.97% C H O requires: C, 60.2; H, 4.69% EXAMPLE 15 l,S-Bis( 2-carboxy-8-chlorochromon-5-yloxy )pentane A mixture of 4.62parts of 1,5 -bis( 2acetyl-3-hydroxyphenoxy) pentane (from Example 6)and 2.7 parts of sulphuryl chloride in 300 parts of dry ether wasstirred for 7 hours at room temperature. The solution was filtered andevaporated to dryness leaving a yellow solid. This was recrystallizedfrom ether to obtain 2.36 parts of1,5-bis(2-acetyl-4-chloro-3-hydroxyphenoxy)pentane as pale yellow prismsmelting at 96 C.

This was condensed with diethyl oxalate as in Example 1 (b) to obtainthe diethyl ester of 1,5-bis(2-carboxy-8-chlorochromon-5-yloxy)pentanemelting between 162 and 164 C from ethanol.

Analysis:

Found: C, 57.7; H, 4.3%

C H Cl o requires: C, 57.5; H, 4.3%

The ester was hydrolyzed as in Example 5 (c) to obtain the acid, meltingat 244 C from ethanol. Analysis:

Found: C, 54.2; H, 4.6; Cl, 12.9%

C, H Cl O requires: C, 54.7; H, 3.28; CI, 12.9%

v The acid was converted to the disodium salt by the method of Examples5 (0). EXAMPLE 16 a. 2-( 2,3-Epoxypropoxy)-6-hydroxyacetophenone To amixture of 5.68 parts of 2,6-dihydroxyacetophenone, 10.3 parts ofepichlorohydrin and 3 parts (by volume) of ethanol which was stirred andgently refluxed, was added slowly a solution of 2.58 parts of potassiumhydroxide in 7 parts (by volume) of ethanol and 1 part (by volume) ofwater. The mixture was then stirred and refluxed for 1 hour, then aftercooling an excess of water was added and the product was extracted intoether and the solution was dried over sodium sulphate. After removingthe drying agent and the solvent 5 parts of a crude oil remained. Thisoil was extracted using hot petrol ether (b.p. 4060) and on coolingyellow crystals of 2-(2,3-epoxypropoxy)-6- hydroxyacetophenone m.p. 6163separated. Analysis:

Found: C, 63.5; H, 5.7%

C l-1 ,0 requires: C, 63.45; H. 5.8%

b. 1-(2-Acetyl-3-hydroxyphenoxy)-3-(4-acetyl-3-hydroxyphenoxy)-2-hydroxypropane.

A mixture of 5 parts of 2-(2,3-epoxypropoxy)-6- hydroxy-acetophenone,3.8 parts of resacetophenone,

20 parts (by volume) of dioxan and 5 drops of trimethyl benzyl ammoniumhydroxide solution were heated at C in a sealed bottle overnight. Aftercooling the product crystallized out and was recrystallized from dioxanto yield 2 parts ofl-(2-acetyl-3-hydroxyphenoxy)-3-(4-acetyl-3-hydroxyphenoxy)-2-hydrox-'ypropane melting between 182 and 185 C. Analysis:

Found: C, 62.8; H, 5.4%

C d-1, 0 requires: C, 63.3; H, 5.6% c.2-(3-Chloro-2-hydroxypropoxy)-6-hydroxyacetophenone A mixture of 10parts of 2,6-dihydroxyacetophenone, 7 parts of epichlorohydrin in 18parts (by volume) of dioxan and 5 drops of Triton B, was heated at 100 Cin a sealed vessel for 2% days. The solvent was then removed underreduced pressure and an excess of ether was added to the residue. Theether solution was decanted from the insoluble, washed with water (2 X50 parts) and 2N sodium carbonate (3 X 25 parts). The solvent wasremoved after drying over sodium sulphate and the residue was purifiedby chromatography using an alumina column and ether as eluent. The oilwas distilled to obtain 2-(3-chloro-2-hydroxypropoxy)-6-hydroxyacetophenone (6 parts) as a yellow oil b.p.1668 at 1.5mm.

Analysis:

Found: C, 53.7; H, 5.26%

C I-1 C requires: C, 54.0; H, 5.32%

d. l-( 2-Acetyl-3-hydroxyphenoxy)-3-(4-acetyl-3-hydroxyphenoxy)-2-hydroxypropane To the above chlorohydrin (6 parts) wasadded 3.8 parts of resacetophenone, 3.5 parts of anhydrous potassiumcarbonate and 50 parts (by volume) of dry acetone. This mixture wasrefluxed for 2 days. Then the insoluble material was filtered, aftercooling, and stirred in water to remove inorganic material.Recrystallization of the residue from dioxan yielded 0.7 parts of1-(2-acetyl-3-hydroxyphenoxy)-3-(4-acetyl-3-hydroxyphenoxy)-2-hydroxypropane melting between 182 and 185 C andidentical with the product from (b) above. From the acetone filtrate afurther 2 parts of this product were obtained.

e.l-(Z-Ethoxycarbonylchromon-S-yloxy)-3-(2-ethoxycarbonylchromon-7-yloxy)-2-hydroxypropane.

By the method of Example 1(b) 1-(2-acetyl-3-hydroxyphenoxy)-3-(4-acetyl-3-hydroxyphenoxy)-2- hydroxypropane wascondensed with diethyl oxalate to form1-(2-ethoxycarbonylchromon-5-yloxy)-3-(2-ethoxycarbonylchromon-7-yloxy)-2-hydroxypropane melting between 193 and194.5 C from ethanol plus dioxan.

Analysis:

Found: C, 62.0; H, 4.3% -hydroxypropane.

(3 1-1 0,, requires: C, 61.8; H, 4.6% F.1-(2-Carboxychromon-5-yloxy)-3-(2-carboxychromon-7-yloxy)-2-hydroxypropene.

The ester from (e) above was hydrolyzed as in Example 5(c) to obtain theacid melting between 194 and 200 C with preliminary softening.

Analysis:

Found: C, 55.2; H, 3.96%

C H G H O requires: C, 54.7; H, 3.9%

This acid was dissolved in an equivalent amount of sodium bicarbonatesolution and freeze-dried to obtain the disodium salt.

EXAWLE 17 a. 1-(2-Acetyl-3-hydroxyphenoxy)-5-(4-acetyl-3-hydroxyphenoxy)pentane A mixture of 5.1 parts of2,6-dihydroxyacetophenone, 7.7 parts of 1,5-dibromopentane, and 2.3parts of anhydrous potassium carbonate in 100 parts (by volume) ofanhydrous acetone was refluxed for 20 hrs. An examination of thismixture by thin layer chromatography showed unchanged 2,6-dihydroxyacetophenone, 1 ,5-bis( Z-acetyl-S-hydroxyphenoxy)pentane and suspected2-(5-bromopentyloxy)-6- hydroxyacetophenone to be present. The acetonesolution was concentrated to half its volume and the residue was removedby filtration. After washing with water this residue yielded 1.9 partsof 1,5-bis(2-acetyl- 3-hydroxyphenoxy)pentane. The filtrate was taken todryness and chromatographed on an alumina column using ether as eluent.The 2-(5-bromo-pentyloxy)-6- hydroxyacetophenone came off in the firstfractions, as confirmed by thin layer chromatography. Evaporation ofthese collected fractions yielded 5 parts as an oil which was used asfollows without further purification. Thus a mixture of 2.4 parts of thecrude oil, 1.2 parts of resacetophenone, 1 part of anhydrous potassiumcarbonate and 40 parts (by volume) of dry acetone was refluxed for 20hrs. After cooling the acetone solution was filtered and evaporated todryness. The residue was crystallized from methanol-water to yield 1.85parts of 1-(2-acetyl-3-hydroxyphenoxy)-5-(4-acetyl-3-hydroxy-phenoxy)pentane melting between 91 and 91.5 C. Analysis:

Found: C, 67.3; H,.6.7%

C H O requires: C, 67.7; H, 6.5%

b.1-(2-Ethoxycarbonylchromon-5-yloxy)-5-(2-ethoxycarbonylchromon-7-yloxy)pentane.

By the method of Example 1(b) l-(2-acetyl-3-hydroxyphenoxy)-5-(4-acetyl-3-hydroxyphenoxy)pentane was condensed withdiethyl oxalate to yield the desired product crystallizing from ethanoland melting between 149 and 152 C.

Analysis:

Found: C, 64.1; H, 5.3%

C ,,H 0 requires: C, 64.9: H, 5.3%

c. 1-( 2-Carboxychromon-5-yloxy)-5-(2-carboxychromon-7-yloxy)pentane To1.0012 parts of the above bis-ester in 30 parts (by volume) of methanolwas added an amount of 0.969N sodium hydroxide in methanol justsufficient for the ester hydrolysis. This mixture was then heated on thesteam-bath for h hr, the solvent was distilled off and the residue wastaken up in water and filtered, the filtrate was then acidified withdilute hydrochloric acid. The solid which separated proved diflicult tofilter and was, therefore, separated from the liquors by centrifuging,washing twice with water and recentrifuging. Thel-(2-carboxy-chromon-5-yloxy)-5-(2-carboxychromon-7-yloxy)pentane (0.25parts) was crystallized from ethanol and had a melting point between 249and 25 1 C with preliminary softening.

Analysis:

Found: C, 60.3; H, 4.4%

C l- 0 11 0 requires: C, 60.2; H, 4.45%

This acid was dissolved in an equivalent amount of sodium bicarbonatesolution and freeze-dried to obtain the disodium salt.

EXAMPLE 18 a. 1 ,3-Bis( 2-acetyl-3-hydroxy-5-methylphenoxy)-2-hydroxypropane.

To a solution of sodium ethoxide in ethanol (from 0.83 parts of sodiumand 20 parts by volume of ethanol) wasadded a solution of 12 parts of2,6- dihydroxy-4-methylacetophenone and 3.34 parts of epichlorohydrin in10 parts (by volume) of ethanol. The resulting mixture was stirred andrefluxed for 4 hrs; after cooling 250 parts of water were added and thesolid was isolated by filtration. Crystallization of this solid fromethanol yielded 4.15 parts of 1,3-bis(2-acetyl-3-hydroxy-5-methylphenoxy)-2-hydroxypropane melting between and186 C.

Analysis:

Found: C, 64.1; H, 6.3%

C l-I 0, requires: C, 6.49; H, 6.2%

b. 1 ,3-Bis( 2-carboxy-7-methylchromon-5 -yloxy)-2- hydroxypropane.

By the method of Example 1(b) the above compound was condensed withdiethyl oxalate to yield 1,3- bis(2-ethoxycarbonyl-7-methylchromon-5-yloxy)-2- T hydroxypropanecrystallizing from ethanol as colorless needles melting between 194 and196 C. The ester was hydrolyzed asin Example 5(c) to obtain the acid asthe monohydrate crystallizing from aqueous dioxan and melting between240 and 241 C.

Analysis:

Found: C, 58.3; H, 4.4%

C H O -H O requires: C, 58.4; H, 4.3%

The acid was subsequently converted to the disodium salt by the methodof Example 5(c).

EXAMPLE 19 a. 1 ,3-Bis( 2-acetyl-4-ethyl-3-hydroxyphenoxy)-2-hydroxypropane.

2,6-Dihydroxy-3-ethylacetophenone was condensed with epichlorohydrin bythe method of Example 18(a) to yield1,3-bis(2-acetyl-4-ethyl-3-hydroxyphenoxy)-2- hydroxypropane meltingbetween 135 and 137 C (from ethanol).

Analysis:

Found: C, 66.7; H, 6.9%

C i-1 requires: C, 66.3; H, 6.8%

b. 1 ,3-Bis( 2-carboxy-8-ethylchromon-5-yloxy)-2- hydroxypropane.

The above compound was condensed with diethyl oxalate as in Example 1(b)to obtain 1,3-bis(2-ethoxycarbonyl-8-ethylchromon-5-yloxy)-2-hydroxypropane melting between 159 and 161 C (from ethanol).

This ester was hydrolyzed as in Example (c) to obtain the acid as thedihydrate crystallizing from ethanol and melting between 193 and 194 C.

Analysis:

Found: C, 57.5; H, 4.9%

C H O -2H O requires: C, 57.85; H, 5.0%

The disodium salt was then prepared as in Example 5(c).

EXAMPLE 20 The activity of the new bis chromonyl compounds has beenevaluated by the antigen inhalation test on human volunteers who sufferfrom specific allergic asthma. The degree of asthma provoked by theinhalation of an antigen to which the volunteers are sensitive can bemeasured by repeated estimation of the increase of air-way resistance.

A suitably designed spirometer was used to measure the forced expiratoryvolume at one second (F.E.V. and hence the changes in the air wayresistance. The anti-allergic activity of a compound is estimated fromthe difference between the maximum per cent F.E.V., reduction followingcontrol and test provocations after drug administration conducted underidentical experimental conditions.

Thus: Percent protection 100 Pro- Compound Under Test tection Disodiumsalt of l,5-bis(2-carboxychromon-5- yloxy )-pentane 30 35 pentane.Disodium salt of l,7-bis( 2-carboxychromon-5- yloxy)-2, 6dihydroxy-4-oxaheptsne. 25 30 Disodium salt of l,4-bis(2-carboxychromon-5-yloxy)butane: 4S 50 Disodium salt of 1,4-bis( Z-earboxychromon-S-yloxy)-2, 3dihydroxy-butane. 4O 45 Disodium salt ofl,4-bis(2-carboxychromon-5- .yloxy)-2-hidroxy-butane. 50 55 Disodiumsalt of l,4-bis(Z-carboxychromon-S- yloxy)-but-2-ene. 45 50 Disodiumsalt of l,l0-bis(2-carboxychromon-5- yloxy-decane. 35 40 Disodium saltof l,6-bis(2-carboxychromon-5- yloxy)-hexane. 45 50 hexane. Disodiumsalt of 1,3-bis(2-carboxychromon-5- yloxy)-2-hydroxypropane. 65 Disodiumsalt of l,3-bis( 2-carboxychromon-5- yloxy)-propane. 40 45 Disodium saltof l,5-bis( 2-carboxy-8-chlorochromon-5-yloxy)pentane 20 25 Disodiumsalt of 1,5-bis( Z-carboxychromon-G- yloxypentane. 20 25 Disodium saltof l,5-bis( 2-carboxychromon-7- yloxy)-pentane. 45 50 Disodium salt ofl,3-bis(2-carboxychromon-7- yloxy)-2-hydroxypropane. 40 45 Disodium saltof l,3-bis(2-carboxy-8-ethylchromon-5-yloxy)-2-hydroxypropane. 20 25Disodium salt of 1,2-bis(Z-carboxychromon-S- yloxyrnethyl)-benzene. 3035 Disodium salt of l-(Z-carboxychromon-S-yloxy)-3-(2-carboxychomon-7-yloxy)- 2-hydroxypropane. 45 50 Disodium salt ofl,3-bis( 2-carboxychromon-6- yloxy)-2-hydroxypropane. 40 45 Disodiumsalt of l,3-bis(2-carboxy-8- methylchromon-7-yloxy)- 2-hydroxypropane.l5 20 Disodium salt of l-( 2-carboxycychromon-S-yloxy 3-(Z-carboxy-Sethyl-chromon-S-yloxy)-T-- hydroxy-propane. 25 30 Dipotassiumsalt of l,3-bis(2-carboxychromon-5-yloxy)-2-chloromethyl-2-hydroxymethylpropane. 40 45 Disodium salt of1,5-bis(2-carboxychromon-5- yloxy)-3-methylpentane. 20 25 Disodlum saltof l-(2-carboxychromon-5-yloxy)-3- (Z-carboxy BZ-hydroxy-propane. 35 40121 2 Disodium salt of l.3-bis(2-carboxychromon-5- yloxy)-acetone. 30 35Disodium salt of l,3-bis(Z-cnIboxychmmon-S' yloxy)-2-ethoxypropsne. 3035 Clinical investigations of 1,3-bis( 2-carboxychromon-5-yloxy)-2-hydroxypropane in the form of its disodium salt, hereinafterreferred to as compound-A, have been carried out on volunteers havingclinical evidence of allergic asthma. In the case of some of thevolunteers this asthma was identified as extrinsic asthma, i.e., wasprovoked by a specific antigen; the majority of the volunteers, however,were classified as suffering from intrinsic asthma, i.e., did notrespond to a large number of skin and aerosol provocation tests.

In the case of the volunteers suffering from extrinsic asthma it waspossible to assess the degree of protection afl'orded quantitativelyusing the test procedure described above.

In the case of subjects suffering from intrinsic asthma the therapeuticeffect of compound A could be assessed subjectively and by objectivetests of lung function.

The results of the clinical investigations may be summarized as follows:

1. Inhalation of compound A in doses of 1-20 mg. re-

peated at 4 to 8'hour intervals is well tolerated; no side effects orother evidence of toxicity being observed during a continuous trialperiod of 5 months.

2. The therapeutic effect of compound A may be apparent in 4 hours butincreases for several days with continued therapy, reaching a maximum inl to 2 weeks. A dose of 2-6 mg. 4 to 6 hourly induces a significantimprovement as shown by objective tests of lung function in mild cases.

In more severe cases, doses of up to 20 mg. at 4 to 6 hourly intervalsare required to produce a significant improvement.

In quantitative objective tests it has been found that compound A,administered in a dose of 20 mg. gives up to 84 percent protection 2hours after administration, up to 70 percent protection 4 hours afteradministration, and noticeable protection, e. g. about 20 percentprotection 18 hours after administration.

Subjective improvement usually includes:

a. Reduction of chest tightness;

b. increased tolerance to exercise; and

c. Reduced sputum volume and cough.

Withdrawal of therapy with compound A was followed by a relapse within48 hours in severe cases or after 7-14 days in mild cases.

The acute i.v. toxicity of compound A, in rats, has been found to below; i.e., the LD is at least 1000 mg/Kg.

What is claimed is: l. A compound of the formula H R out-c in which R, RR, R, R and R are each selected from the group consisting of hydrogen,halogen, hydroxy, lower alkyl, lower alkoxy, hydroxylower alkyl,haloloweralkyl, hydroxyloweralkoxy, and loweralkoxyloweralkoxy and X isselected from the group consisting of straight and branched, saturatedand unsaturated hydrocarbon chains which are uninterrupted orinterrupted by a member selected from the group consisting of benzene,oxygen and carbonyl and are unsubstituted or substituted by a member ofthe group consisting of halogen or hydroxy and lower alkoxy, with theproviso that when R, R R, R, R and R are hydrogen, X is not the group CH-CHOH--CH linking the two positions para to the acetyl groups. 2. Acompound of the formula in which R, R, R, R, R and R are each selectedfrom the group consisting of hydrogen, halogen, hydroxy. lower alkyl,lower alkoxy, hydroxylower alkyl, haloloweralkyl, hydroxyloweralkoxy,and loweralkoxyloweralkoxy, and X represents a saturated hydrocarbonchain which is unsubstituted or which is substituted by a member of thegroup consisting of halogen, hydroxy or lower alkoxy with the provisothat when R, R R R, R and R are hydrogen, X is not a group CH CHOHCHlinking the two positions para to the acetyl groups.

3. A compound according to claim 2 wherein X represents the group 4. Acompound according to claim 3, said compound being1,3-bis(2-acetyl-3-hydroxyphenoxy)-2-hydroxypropane.

, UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No.3,686,320 Dated August 2, 1972 Inventor(s) COLIN FITZMAURICE and THOMASBRIAN LEE It is certified that error appears in the above-identifiedpatent and that said Letters Patent are hereby corrected as shown below:

In column 1, below [21] Appln. No. 762,63 8" insert the following:

- [30] Foreign Application Priority Data March 25', 1965 Great Britain12626/65 December 9, l965 Great Britain 524l4/65- Signed and sealed this13th day of November 1973.

(SEAL) Attest:

EDWARD M.PLETCHER,JR. Y RENE D. TEGTMEYER v Attestlng Officer. ActingCommissioner of Patents USCQMM-DC 60376-P 6 9 1- u s. covzmmcm Pmynngg oFlcg; x959 0-366-334.

2. A compound of the formula in which R1, R2, R3, R4, R5 and R6 are eachselected from the group consisting of hydrogen, halogen, hydroxy, loweralkyl, lower alkoxy, hydroxylower alkyl, haloloweralkyl,hydroxyloweralkoxy, and loweralkoxyloweralkoxy, and X represents asaturated hydrocarbon chain which is unsubstituted or which issubstituted by a member of the group consisting of halogen, hydroxy orlower alkoxy with the proviso that when R1, R2, R3, R4, R5 and R6 arehydrogen, X is not a group -CH2-CHOH-CH2-linking the two positions parato the acetyl groups.
 3. A compound according to claim 2 wherein Xrepresents the group
 4. A compound according to claim 3, said compoundbeing 1,3-bis(2-acetyl-3-hydroxyphenoxy)-2-hydroxypropane.